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Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor

a polymerases and inhibitor technology, applied in the field of 8fluoro2 4(methylamino) methylphenyl 1, 3, 4, 5tetrahydro6hazepino5, 4, 3cdindol6one, can solve the problems of inability to meet the needs of patients, inability to respond well to cytotoxic chemotherapy agents or regimens, and significant toxicity in conjunction with suboptimal efficacy

Inactive Publication Date: 2006-04-06
AGOURON PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0042] The term “radio-immunotherapy”, as used herein, means radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy).

Problems solved by technology

However, for patients with advanced or metastatic disease, few of the cytotoxic chemotherapy agents or regimens have been effective in increasing overall survival.
Furthermore, the small therapeutic window associated with cytotoxic agents results in significant toxicity in conjunction with suboptimal efficacy.
However, even in front-line treatment of cancers, in which radiotherapy is administered with curative intent (for example, head and neck cancer, soft tissue sarcoma and carcinoma of the cervix), not all patients respond well.

Method used

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  • Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor
  • Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor
  • Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of Poly-ADP-Ribose Polymerase

[0228] Crystallographic analysis of the compound of formula 1 bound to the inhibited target enzyme revealed that the drug binds to the active site of PARP-1, forming 3 hydrogen bonds. The PARP enzyme inhibiting activity of the compound of formula 1 was assayed as described in U.S. Pat. No. 6,495,541. The Ki determined using 32P-NAD+ incorporation into polymer by purified full-length human PARP-1, is 1.4 nM (Table 3). The compound of formula 1 is also a potent inhibitor of PARP-2 (Ki=0.17 nM) and, based on strong structural similarities in the amino acid sequences among the various PARP family enzymes (tankyrase, V-PARP), the phosphate salt of the compound of formula 1 (Compound I) will likely bind with high affinity to these enzymes as well.

TABLE 3Kinetic Constants for the Interaction of the Compound ofFormula 1 with PARPPARP-1 KiPARP-2 KiCompound(nM ± SD*)(nM ± SD*)compound of1.4 ± 0.20.17 ± 0.05formula 1

*SD = standard deviation.

example 2

Inhibition of Cell Growth

[0229] The intrinsic growth inhibitory activity of the compound of formula 1 following 5-day continuous exposure (Table 4) was determined in A549, LoVo and SW620 cell lines as described in U.S. Pat. No. 6,495,541. GI50 values (the concentration required to inhibit growth by 50%) ranged from 7 to 12 μM. Similarly, the ability of 0.4 μM the compound of formula 1 (ie, 50) to increase the growth inhibitory potency of temozolomide and topotecan was determined (Table 2). The potentiation factor at the IC50 concentration; PF50, is calculated as: GI50 temozolomide or topotecan alone / GI50 temozolomide or topotecan+0.4 μM the compound of formula 1. There was an 8-fold decrease in the GI50 of temozolomide in the LoVo cells and a 3.5-fold decrease in the GI50 of temozolomide in A549 cells upon addition of 0.4 μM the compound of formula 1. There was a 1.6-fold decrease in the GI50 of topotecan in the LoVo cells and a 2.6-fold decrease in the IC50 of topotecan in both A5...

example 3

Chemosensitization of Standard Chemotherapeutic Agents by Compound I

[0230] In vitro studies of human tumor cells lines carried out according to the procedure described in U.S. Pat. No. 6,495,541 have shown that at sub-micromolar concentrations the compound of formula 1 enhances the sensitivity of cells to temozolomide and the type-1-topoisomerase inhibitors, topotecan and SN-38 (the active metabolite of irinotecan) against human H460 non-small cell lung cancer (NSCLC) cells (Table 5).

TABLE 5Effect of the compound of formula 1 as a Glucuronate Salt onthe In Vitro Potency of Standard Chemotherapeutic Agents inHuman H460 NSCLC CellsChemotherapeuticAgentTypesPF50 (H460)aPaclitaxelMicrotubule antagonist0.775-FluorouracilPyrimidine antagonist0.92GemcitabinePyrimidine antagonist1.26-thioguaninePurine antagonist1.1DoxorubicinAnthracycline antibiotic1.1OxaliplatinPlatinum compound0.98bCisplatinPlatinum compound1.2EtoposideTopoisomerase II inhibitor0.75bTopotecanTopoisomerase I inhibitor1....

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Abstract

This invention generally relates to use of 8-fluoro-2{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one represented by formula 1 as a chemosensitizer that enhances the efficacy of cytotoxic drugs or radiotherapy. This invention provides pharmaceutical combinations of 8-fluoro-2{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, kits containing such combinations and methods of using such combinations to treat subjects suffering from diseases such as cancer.

Description

[0001] This application claims the benefit of U. S. Provisional Application No. 60 / 612,458 filed on Sep. 22, 2004, and U.S. Provisional Application No. 60 / 683,006 filed on May 19, 2005, the contents of which are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION [0002] This invention generally relates to use of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one as a chemosensitizer that enhances the efficacy of cytotoxic drugs or radiotherapy. This invention provides pharmaceutical combinations of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, kits containing such combinations and methods of using such combinations to treat subjects suffering from diseases such as cancer. BACKGROUND OF THE INVENTION [0003] The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahyd...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55A61K33/243A61K33/244
CPCA61K31/282A61K31/4188A61K31/4745A61K31/513A61K31/519A61K31/55A61K31/704A61K33/24A61K41/00A61K2300/00A61K31/495A61P1/04A61P1/18A61P11/00A61P13/02A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P25/00A61P27/02A61P35/00A61P35/02A61P43/00A61P5/14A61P5/18A61K33/243A61K33/244
Inventor STEINFELDT, HEIDI MARIEBORITZKI, THEODORE JAMESCALVERT, ALAN HILARYCURTIN, NICOLA JANEDEWJI, MOHAMED RAZAHOSTOMSKY, ZDENEKJONES, CHRISTOPHERKAUFMAN, RHONDAKLAMERUS, KAREN J.NEWELL, DAVID RICHARDPLUMMER, ELIZABETH RUTHREICH, STEVEN D.STRATFORD, IAN J.THOMAS, HUW DAVIDWILLIAMS, KAY JANINE
Owner AGOURON PHARMA INC
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